5-arylsulfamyl-anthranilic acids

ABSTRACT

R1=ALIPHATIC OR ARALIPHATIC RADICAL R2=H OR R1 R3=CL OR BR AND FUNCTIONAL DERIVATIVES THEROF, EXHIBIT DIURETIC EFFECTS.   1-(PHENYL-NH-SO2-),2-R3,4-(R1-N(-R2)-),5-(HOOC-)BENZENE   5-ARYLSULFAMYL-4-HALO-ANTHRANILIC ACIDS, E.G. THOSE OF THE FORMULA

"United States Patent Office 3,806,542 Patented Apr. 23, 1974 3,806,542S-ARYLSULFAMYL-ANTHRANILIC ACIDS Lincoln Harvey Werner, Summit, N.J.,assignor to Ciha- Geigy Corporation, Ardsley, N.Y.

No Drawing. Continuation-impart of application Ser. No. 832,029, June10, 1969, which is a continuation-in-part of abandoned application Ser.No. 675,330, Oct. 16, 1967, which in turn is a continuation-in-part ofabandoned application Ser. No. 598,980, Dec. 5, 1966. This applicationNov. 19, 1970, Ser. No. 91,224

Int. Cl. C07c 143/80 US. Cl. 260--518 A 6 Claims ABSTRACT OF THEDISCLOSURE 5-arylsulfamyl-4-halo-anthrauilic acids, e.g. those of theformula HNOzS- o OH R NR t,

R =aliphatic or araliphatic radical R2==H 01' R1 R =Cl or Br andfunctional derivatives thereof, exhibit diuretic effects.

CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-partof application Ser. No. 832,029, filed June 10, 1969 (now Pat. No.3,658,990), which in turn is a continuation-in-part of application Ser.No. 675,330, filed Oct. 16, 1967 (now abandoned), which in turn is acontinuation-in-part of application Ser. No. 598,980, filed Dec. 5, 1966(now abandoned).

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new -arylsulfamyl-4-halo-anthranilic acids andtheir therapeutically acceptable derivatives, more particularly those ofFormula I,

R5-III 028 C O O H R N--IIR1 in which each of R R and R stands for analiphatic or araliphatic radical, R and R also for hydrogen, R forchloro or bromo and R for a carbocyclic or heterocyclic aryl radical,esters, amides, acyl derivatives and/or salts thereof, as Well as ofcorresponding pharmaceutical compositions, new starting materials andmethods for the preparation and application of these products. Saidcompositions are primarily useful as orally applicable diuretic,natriand chloriuretic agents in order to relieve excessive water and/orsalt retention, for example, in connection with heart and kidneydiseases, and in the adjunctive management of hypertension.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The aliphatic or araliphaticradicals mentioned for R R and R are hydrocarbon radicals, which may besubstituted by functional groups and/or interrupted by heteroatoms, suchas nitrogen, oxygen and/or sulfur atoms. Such radicals are, for example,lower alkyl, e.g. methyl, ethyl, nor i-propyl, n-, i-, or sec.butyl, nori-pentyl, neopentyl, n-hexyl or n-heptyl, lower alkenyl, e.g. vinyl,allyl, methylallyl or 2-butenyl, lower alkynyl, e.g. propargyl, monoorbicyclic cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl orcycloalkenyl-lower alkyl with preferably 5 to 7 ring-carbon atoms, 1 to4 chain carbon atoms and optional, e.g. up to 4, lower alkyl groups,e.g. cyclopropyl, 2,3-dimethyl-cyclopropyl, cyclobutyl, cyclopentyl, 2-or 3-methyl-cyclopentyl, 2,5- or 3,4-dimethyl-cyclopentyl, cyclohexyl,2-, 3- or 4-methyl-cyclohexyl, 2,3-, 2,4- or 3,5-dimethyl-cyclohexyl,2,4,6-trimethyl-cyclohexyl, cycloheptyl, cyclooctyl, 2- or7-norbornanyl, 1- or 2- decahydronaphthyl; 1- or 2-cyclopentyl,2,4-cyclopentadienyl, 2- or 3-methyl-2-cyclopentenyl, 4,5-dimethyl-2-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 2,5-cyclohexadienyl, 2-, 3- or4-methyl-1- or 2-cyclohexenyl, 2,4- or 3,5-dimethyl-1- or2-cyclohexenyl, 2,4,6-trimethyl-2,5-cyclohexadicnyl, 1-, 2- or3-cycloheptenyl, 2,6-cycloheptadienyl, 2-cyclooctenyl or 2-norborn5-eny1, as well as the corresponding cycloalkylor cycloalkenyl-loweralkyl groups in which the chain especially represents methyl, but alsoethyl nor i-propyl, n-, ior see. butyl; it contains in any of thepositions available for substitution one of the specific cycloalkyl orcycloalkenyl groups listed above. The term lower, referred to above andhereinafter in connection with organic radicals or compoundsrespectively, defines such with up to 7, preferably up to 4, carbonatoms. Aliphatic radicals that are substituted, e.g. by free orfunctionally converted hydroxy, mercapto or carboxy groups and/0rinterrupted by hcteroatoms, e.g. one oxygen, sulfur and/or nitrogenatom, are represented, for example, by lower haloalkyl, e.g. 2-(chloro,bromo or iodo)-ethyl, 3,3-difiuoroor -dichloropropyl, 3,3,3-trichloropropyl, 3- or 4-chlorobutyl, 4,4- or 3,4-dichlorobutyl or4,4,4-triflu0robutyl; unsubstituted or halogenated lower alkoxyoralkylmercapto-lower alkyl, such as 2- ethoxyethyl, 3-methoxy-propyl,Z-ethyhnercapto-ethyl, 2- (2,2 dichloroethoxy)-ethyl,2-(2-chloroethoxy)-ethyl, 2- (2,2,2-trifluoroethylmercapto) ethyl or2-(2,2-dichloroethylmercapto)-ethyl; carbamyl-lower alkyl or N,N-diloweralkylcarbamyl-lower alkyl, such as carbamyl-methyl,N,N-dimethylcarbamyl-methyl, Z-carbamyl-ethyl or 2-N,N-diethylcarbamyl-ethyl; sec. or tert. amino-lower alkyl, such asmonoor di-lower alkylamino-lower alkyl, lower alkyleneimino-lower alkyl,lower monoaza-, oxaor -thiaalkyleneimino-lower alkyl or -N-loweralkyl-lower monoazaalkyleneimino-lower alkyl, e.g. Z-ethylaminoethyl,Z-dimethylamino-ethyl, 3-dicthylamino-propyl, 2- pyrrolidino-ethyl,Z-piperidino-ethyl, 2-(4-methyl-piperazino)-ethyl or 2-morpholino-ethyl,5 to 7 ring-membered oxa-cycloalkyl or -cycloalkenyl, oxa-cycloalkylor-cycloalkenyl-lower alkyl, such as S-tetrahydrofuryl,tetrahydrofuryl-Z-methyl, (2 methyl-tetrahydrofuryl-Z)-methyl,2,3-dihydroor tetrahydropyranyl-Z-methyl.

R and R when taken together, may also represent lower alkylene oralkenylene, e.g. 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,4- or1,5-pentylene, 1,5, 2,5- or 1,6- hexylene or 2,6-heptylene;1,4-but-2-enylene, 1,4- or 1,5- pent-2-enylene, 1,5-hex-2-enylene,1,6-hex-3-enylene or 2,6-hept-3-enylene; lower monoaza-, oxaor-thiaalkylene or N-lower alkyl-monoaza-lower alkylene, e.g. 3-aza, 3-oxaor 3thia-pentylene-( 1,5), 3-methylor 3-ethyl-3- aza-pentylene-(1,5),3-aza-hexylene-(1,6) or 4-azaor oxa-heptylene-(2,6). In thealiphatically substituted group two hcteroatoms, e.g. nitrogen, oxygenand/or sulfur atoms, are separated by at least 2 carbon atoms.

An araliphatic radical R R and R preferably stands for monoor bicycliccarbocyclic aryl-lower alkyl or aryllower alkenyl, especially (monoordi-R -phenyl)-lower alkyl or -alkeny1, but also for monoor bicyclicheterocyclic, especially monoaza-, oxaor thiacyclic aryl-lower alkyl oraryl-lower alkenyl in which the alkyl or alkenyl moiety preferably hasup to 4 chain carbon atoms, and the aromatic portion is unsubstituted orsubstituted by one or more than one, preferably 1 or 2, substituentsselected, for example, from lower alkyl, e.g. that mentioned above,phenyl, free or functionally converted hydroxy or mercapto, such aslower alkoxy, lower alkylenedioxy, lower alkylmercapto or halogeno, e.g.methoxy, ethoxy, nor i-propoxy or -butoxy, methylenedioxy, 1,1- or1,2-ethylenedioxy, methylor ethylmercapto, fluoro, chloro or bromo;(hydroxy or halogeno)-lower alkyl or -alkoxy, e.g. 2 hydroxyethyl,trifluoromethyl or 2-hydroxyethoxy, nitro, amino, especially diloweralkylamino, e.g. dimethylamino or diethylamino, sulfamoyl, or free orfunctionally converted carboxy, e.g. lower carbalkoxy, carbamoyl orcyano. Preferred aryl-substituents R are hydrogen, lower alkyl,hydroxy-lower alkyl, hydroxy, mercapto, lower alkoxy, loweralkylmercapto, hydroxylower alkoxy, halogeno, trifluoromethyl, nitro,amino, dilower alkylamino, carboxy and/ or lower carbalkoxy.Unsubstituted carbocyclic aralkyl or aralkenyl radicals are exemplifiedby benzyl, 1- or Z-phenylethyl, l-, 2- or 3- phenyl-propyl,Z-phenyl-Z-propyl, 1-, 2-, 3- or 4-phenylbutyl, 1- or 2-phenyl-2-butyl,styryl or cinnamyl. In the corresponding heterocyclic aralkyl oraralkenyl radicals aryl is preferably monocyclic monoaza, -oxaor-thiacyclic aryl, e.g. 2-, 3- or 4-pyridyl, 2- or 3-furyl or -thienyl,but also 5-(l,2-oxazolyl), 2-( l-oxazolyl), 2-(1,3-thiazolyl),6-thianaphthyl or Z-benzimidazolyl. Araliphatic radicals are alsopartially hydrogenated, preferably bior tricyclic aryl radicals, boundat the aliphatic portion, such as 1- or 2-indolinyl, 1- or2-(l,2,3,4-tetrahydronaphthyl) or 9-fluorenyl.

The radical R preferably stands for monoor bicyclic carbocyclic orheterocyclic aryl, e.g. that mentioned for the above araliphaticradicals. It especially represents monoor di-R -phenyl, in which R hasthe meaning given above.

Esters and amides of the compounds of Formula I are particularly loweralkyl esters, the amide, monoor diloweralkyl-amides (hydroxy or loweralkoxy)-lower alkyl esters or amides (amino, monoor di-loweralkylamino)- lower alkyl esters or amides, wherein two heteroatoms areseparated by at least 2, preferably 2 or 3, carbon atoms, e.g. themethyl, ethyl, nor i-propyl or -butyl ester, the amide, monoordimethylamide, diethylamide or i-propylamide, the Z-(hydroxy ormethoxy)-ethyl ester or amide, Z-(amino, monoor dimethylamino)-ethylester or amide or 3-dimethyl-amino-propyl ester or amide, or aralkylesters, such as (R -phenyh-lower alkyl, e.g. benzyl, 1- or 2- phenethylesters.

The acyl derivatives are preferably those of lower alkanoic acids, suchas acetic, propionic, butyric or pivalic acid, but also of loweralkenoic acids, such as acrylic or methacrylic acid, or of R-phenyl-lower alkanoic or -alkenoic acids, such as benzoic, phenylaceticor cinnamic acid. The acyl group therein is preferably attached to aprimary, but also a secondary amino group and/or a free hydroxy ormercapto group.

The compounds of the invention exhibit valuable pharmacologicalproperties. Primarily they show diuretic, natriand chloriuretic activitywith rapid onset of action, high urine but low potassium excretionlevels. This can be demonstrated in animal tests using, for examplemammals, e.g. rats or dogs, as test objects. Such tests can beperformed, for example, by administering the compounds of the inventionWithin a gelatin capsule to dogs, or in the form of aqueous solutions orsuspensions by stomach tube to rats, in an oral dosage range betweenabout 0.1 and 100 mg./kg./day, preferably between about 0.3 and 50mg./kg./day, advantageously between about 1 and 5 mg./ kg./ day.Simultaneously the test animals may receive various salt loads enterallyor parenterally, for example, various amounts of subcutaneously applied0.9% saline, e.g. 100 ml. thereof per medium-sized dog (beagle). Urineis then collected, e.g. at 2 hour interval with Or Withoutcatheterization, and its volume, sodium, potassium and chloride contentestimated and compared with that of the same untreated or saline-treatedanimals. Besides the above-mentioned utility, the compounds of theinvention can also be used as intermediates in the preparation of othervaluable products, primarily of pharmacologically active compounds.

Preferred are those compounds of Formula I in which R, is lower alkyl,lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenyl-alkyl, oxa-cycloalkyl or -cycloalkenyl, oxacycloalkylor-cycloalkenyl-lower alkyl, with 5 to 7 ring-carbon and 1 to 4 chaincarbon atoms, lower fluoroor chloralkyl, lower alkoxyoralkylmercaptolower alkyl, lower fluoroor chloro-'alkoxyor-alkylmercapto-lower alkyl, di-lower alkylaminoorlower-alkyleneimino-lower alkyl, R and R are hydrogen, lower alkyl or(monoor di-R -phenyl)-alkyl with 1 to 4 chain carbon atoms, R is chloroand R is monoor di-R -phenyl or unsubstituted or lower alkyl-substitutedmonocyclic monoaza-, -oxaor -thiacyclic aryl, preferably pyridyl, furylor thienyl, or especially those compounds of Formula I, in which R -Rhave the meaning given in this paragraph and R is (monoor di-R-phenyb-alkyl or unsubstituted or lower alkyl-substituted monocyclicmonoaza-, -oxa-or -thiacyclic arylalkyl With 1 to 4 chain carbon atoms,or lower alkanoyl derivatives of compounds containing a primary orsecondary amino group, or lower alkyl esters, the amide, monoordi-lower-alkylamides (hydroxy or lower alkoxy)-lower alkyl esters oramides (amino, monoor di-lower alkylamino)-lower alkyl esters or amides,wherein two heteroatoms are separated by at least 2 carbon atoms, thealkali metal, alkaline earth metal or ammonium salts of said anthranilicacids, or acid addition salts of basic compounds.

Especially valuable are the compounds of Formula II in which each of R,and R is phenyl, monoor di-lower alkylphenyl, lower hydroxyalkylphenyl,monoor dihydroxyphenyl, lower alkyl-hydroxyphenyl, monoordimercaptophenyl, monoor di-lower alkoxy-phenyl, loweralkoxy-hydroxyphenyl, lower hydroxyalkoxyphenyl, monoor di-loweralkylmercaptophenyl, monoor di-halogenophenyl, trifluoromethylphenyl,nitrophenyl, monoor diaminophenyl, di-lower alkylaminophenyl, loweralkanoylaminophenyl, carboxyphenyl, lower carbalkoxyphenyl, pyridyl,lower alkylpyridyl, furyl, lower alkylfuryl, thienyl, loweralkylthienyl, tetrahydrofuryl, lower alkyltetrahydrofuryl,dihydropyranyl or lower alkyldihydropyranyl, and each of R and R ishydrogen or lower alkanoyl, the lower alkyl esters, the amide, monoordi-loweralkylamides (hydroxy or lower alkoxy)-loWer alkyl esters oramides, (amino monoor di-lower alkylamino) -lower alkyl esters oramides, wherein two heteroatoms are separated by at least 2 carbonatoms, the alkali metal, alkaline earth metal, ammonium or acid additionsalts thereof.

Outstanding are the compounds of Formula II, in which R; is phenyl,2-furyl, Z-thienyl, Z-tetrahydrofuryl, Z-methyl-2-tetrahydrofuryl or2,3-dihydro-2-pyranyl, each of R and R is hydrogen or acetyl and R isphenyl, monoor dimethylphenyl, 2-hydroxyethylphenyl, monoordihydroxyphenyl, methylhydroxyphenyl, mercaptophenyl, monoordimethoxyphenyl, methoxy-hydroxyphenyl, 2- hydroxyethoxyphenyl,fiuorophenyl, chlorophenyl, trifluoromethylphenyl, nitrophenyl, monoordiaminophenyl, dimethylaminophenyl, acetylaminophenyl, carboxyphenyl,carbomethoxyphenyl or carbethoxyphenyl, the methyl or ethyl ester,3-dimethylaminopropylamide, the sodium potassium or2-hydroxyethylammonium salts of the carboxylic acids or thehydrochlorides of the monoor diamino or dimethylamino compounds.

Most preferred are the N-furfuryl-S-phenylsulfamyl- 4-chloro-anthranilicacid and the N-furfuryl-5-(4-hy droxy-, methoxyoramino-phenylsulfamyl)-4-chlor0- anthranilic acid and their sodium orZ-ethanolammonium carboxylic acid salts or the hydrochloride of the4-aminophenyl compound which, when given to dogs at oral doses betweenabout 1 and 5 mg./ kg./ day, exhibit high diuretic, natriandchloriuretic effects.

The compounds of the invention are prepared according to methods inthemselves known. Advantageously they are obtained by converting in acompound of the Formula III R; (III) in which X stands for a groupcapable of being converted into the amino group Bali-R.

an ester, halide, amide, hydrazide, acyl derivative or salt thereof, Xinto Ih-llI-Rz and hydrolyzing any resulting amide or hydrazidedifferent from such defined above and, if desired, converting anyresulting compound into another compound of the invention.

Any ester, amide, hydrazide or acyl derivative used as starting materialmay be such as described above for the final products. Generally, theamides or hydrazides used as stating material may be N-unsubstituted orN-substitu'ted, for example, by one or more than one aliphatic,araliphatic or aromatic radical, e.g. any of those described above.

The group X, capable of being converted into R1'-I!IRI is preferably ahalogen atom, advantageously fluoro or chloro, but also primary amino oran imino group, forming after reduction (of the corresponding Schifisbase) the goup R NH. The starting material, in which X stands forhalogeno, is reacted with the amine that in which X stands for NH isreacted with a reactive ester of the alcohol R -0H, e.g. such of ahydrohalic or sulfonic acid, e.g. hydrochloric, hydrobromic, hydriodic,methane-, ethane-, benzeneor p-toluenesulfonic acid, whereas thatstarting material, in which X stands for said amino group, is subjectedto hydrogenation, for example, with the use of catalytically activatedor nascent hydrogen.

The above process is carried out according to standard methods, in thepresence or absence of diluents, preferably such as are inert to thereagents and are solvents thereof, of catalysts, condensing agentsand/or inert atmospheres, at low temperatures, room temperature oradvantageously elevated temperatures, at atmospheric or superatmosphericpressure.

In the above reaction the amine reagent is advantageously used inexcess, in order to neutralize any generated acid. It may however, alsobe used in equivalent amounts and in the presence of other condensingagents such as inorganic or organic bases, e.g. alkali metal carbonatesor bicarbonates or tertiary nitrogen bases, for example tri-loweralkylamines, N,N-dimethyl-aniline or pyridine.

Any resulting amide or hydrazide can be hydrolyzed in the usual manner,for example, with the use of a base, e.g. an aqueous alkali or alkalineearth metal hydroxide, or a quaternary ammonium hydroxide. The compoundsof the invention so obtained may be converted into each other accordingto known methods. For example, resulting compounds in which R and/or Rstands for hydrogen, may be reacted with a reactive ester of acorresponding alcohol, for example that of a hydrohalic or sulfonicacid. Resulting compounds with a hydroxy, prim. or sec. amino group maybe acylated, for example, with a reactive functional derivative of acorresponding acid, such as a halide or anhydride thereof, e.g. thionylor acetyl chloride or acetanhydride, resulting acyl derivatives oresters may be hydrolyzed, for example with the use of acidic or alkalinehydrolyzing agents, resulting esters may be transesterified or reactedwith corresponding amines or resulting acids esterified or amidated inknown manner.

The compounds of the invention are obtained in the free form or in theform of their salts, depending on the conditions under which the processis carried out, the salts are also included in the present invention.These are particularly derived from the free acids and therapeuticallyuseful inorganic or organic bases, primarily the alkali metal, alkalineearth metal, e.g. sodium, potassium, magnesium or calcium salts, orammonium salts derived from ammonia or amines, such as thosecorresponding to the amino group e.g. mono-, dior tri-lower alkylamines,-cycloalkylamines, -cycloalkyl-lower alkylamines or -aralkylamines,mixed amines or tertiary nitrogen bases, such as pyridine, collidine orlutidine. Resulting compounds that contain basic groups, e.g. aminogroups, may also form acid addition salts, preferably such oftherapeutically useful acids, such as mineral acids, e.g. hydrochloric,hydrobromic, sulfuric, phosphoric, nitric or perchloric acid; aliphaticor aromatic carboxylic or sulfonic acids, e.g. formic, acetic,propionic, succinic, glycolic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxyrnaleic, pyroracemic, phenylacetic, benzoic,4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic,4-aminosalicylic, em-bonic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, ethylenesulfonic, halogen-benzenesulfonic,toluenesulfonic, naphthalenesulfonic and sulfanilic acid; methionine,tryptophane, lysine and arginine.

The invention further includes any variant of the pres ent process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Mainlythose starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being especially valuable.

The starting material is new and, therefore, a further object of thepresent invention. It can be prepared according to known methods, forexample, a corresponding 2,4- dihalo-benzoic acid is reacted withchlorosulfonic acid in order to yield the2,4-dihalo-S-chlorosulfonyl-benzoic acid. The latter, or a functionalderivative thereof, is then reacted with the amine R -NHR in order toobtain the compounds of Formula III in which X stands for halogeno, orfunctional derivatives thereof. The latter, e.g. the esters, halides,amides or hydrazides, may also be prepared from the acids of Formula IIIby conventional methods. The resulting 2,4-dihalo-S-sulfamyl-benzoicacids may be reacted with ammonia in order to obtain the startingmaterial in which X represents NH which further may be reacted with acorresponding aldehyde or ketone, in order to obtain the startingmaterial in which X stands for an imino group.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulosc, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders oreffervescent mixtures and/ or (e) adsorbents, colorants, flavors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously fattyemulsions or suspensions. They may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/r buffers. They may also contain other therapeutically valuablesubstances. Said pharmaceutical compositions are prepared according toconventional mixing, granulating or coating methods respectively andcontain about 0.1 to 75%, preferably about 1 to 50% of the activeingredient.

The following examples illustrating the invention are not to beconstrued as being limitations thereon. Temperatures are given indegrees centigrade and all parts wherever given are parts by weight.

EXAMPLE 1 The mixture of 2.4 g. 2,4-dichloro--phenylsulfamylbenzoicacid, ml. 2-ethoxy-ethanol and 2.7 g. furfurylamine is refluxed for 4hours under nitrogen. After cooling to room temperature it is pouredinto 50 ml. 2 N-hydrochloric acid. The supernatant liquid is decantedoff and the residue dissolved in 50 ml. 2 N aqueous sodium hydroxide.The solution is extracted twice with diethyl ether and acidified withhydrochloric acid. The precipitate formed is filtered off andrecrystallized from ethanol to yield theN-furfuryl-5-phenylsulfamyl-4-chloroanthranilic acid of the formulaUHNO2S\/COOH T 01 NH-cH/ o melting at 210-212" (dec.).

The starting material is prepared as follows: To 250 g. chlorosulfonicacid 50 g. 2,4-dichloro-benzoic acid are added portion-wise at roomtemperature while stirring. The solution obtained is heated to about 180and stirred for 3 hours. After cooling to room temperature, it is pouredinto ice, the mixture filtered, the residue washed with water, anddissolved in 400 ml. ethyl acetate. The solution is dried, filtered,evaporated, and the residue triturated with hexane, to yield the2,4-dichloro-5-chlorosulfonyl-benzoic acid.

The mixture of 5.8 g. thereof, 7.5 g. aniline and 50 ml. ethyl acetateis stirred for 4 hours at room temperature. It is then filtered and theresidue washed with ethyl acetate. The filtrate is evaporated in vacuoand the residue triturated with 2 N hydrochloric acid. The aqueoussolution is decanted ofl and the precipitate dissolved in 100 ml. 10%aqueous potassium carbonate. The solution is filtered to yield residueA. The filtrate is extracted with diethyl ether and the aqueous layeracidified with hydrochloric acid. The precipitate formed is filteredoil, washed with water and recrystallized from aqueous ethanol to yieldthe 2,4-dichloro-5-phenylsulfamylbenzoic acid melting at 211-213.Residue A is also recrystallized from aqueous ethanol to yield the2,4-dichloro-S-phenylsulfamylbcnzoic acid phenylamide melting at173-475".

EXAMPLE 2 The mixture of 3.0 g. N-furfuryl-5-phenylsulfamyl-4-chloro-anthranilic acid phenylamide, ml. 2 N-aqueous sodium hydroxide,10 ml. water and 10 ml. 2-methoxyethanol is refluxed for 3 hours undernitrogen andallowed to stand at room temperature overnight. It is pouredinto 60 ml. 2 N hydrochloric acid, the precipitate formed filtered off,washed with water and dissolved in 35 ml. 10% aqueous potassiumcarbonate. The solution is extracted with ethyl acetate, the aqueouslayer separated and acidified with hydrochloric acid. The precipitateformed is filtered ofi', recrystallized from aqueous ethanol to yieldthe N-furfuryl-S-phenylsulfamyl-4-chloro-anthraanilic acid melting at212214 with decomposition; it is identical with the compound obtainedaccording to Example 1.

The starting material is prepared as follows: The mixture of 6.0 g.2,4-dichloro-S-phenylsulfarnyl-lbenzoic acid phenylamide, 5.6 g.furfurylamine and 20 ml. 2-methoxyethanol is refluxed for 4 hours undernitrogen and allowed to stand overnight at room temperature. It ispoured into ml. 2 N-hydrochloric acid, the precipitate formed filteredoff and the residue dissolved in diethyl ether. The solution is Washedwith 0.5 N hydrochloric acid, with 10% aqueous potassium carbonate andwater, dried, filtered and evaporated in vacuo, to yield theN-furfuryl-S-phenylsulfamyl-4-chloro-anthranilic acid phenylamidemelting at 114-117.

EXAMPLE 3 Substituting in Example 1 the furfurylamine by the equivalentamount of benzylamine and performing the reaction as shown therein, theN-benzyl-5-phenylsulfamyl- 4-chloroanthranilic acid of the formula.

HNOzS- COOH Ol-- NHCH:

is obtained, M.P. '226228 (from aqueous ethanol).

EXAMPLE 4 The mixture of 3.1 g.2,4-dichloro-5-(4-methyl-phenylsulfamyl)-benz0ic acid, 3.4 g.furfurylamine and 10 ml. 2- methoxyethanol is refluxed for 4 hours undernitrogen. After cooling to room temperature, it is treated with 2 N-hydrochloric acid, the precipitate formed separated and dissolved in 2N-aqueous sodium hydroxide. The solution is extracted with diethylether, the aqueous layer separated and acidified with hydrochloric acid.The precipitate formed is filtered off and recrystallized from aqueousethanol to yield theN-furfuryl-4-chloro-5-(4-methylphenylsulfamyl)-anthranilic acid of theformula C 0 O H NHOzS- H3 0 C1 NH 'CHI LO u melting at 218-220.

The starting material is prepared as follows: To the solution of 5.8 g.2,4-dichloro 5-chlorosulfonyl benzoic acid in 50 ml. ethyl acetate, 8.6g. p-toluidine are added while stirring, followed by 100 ml. ethylacetate. The mixture is stirred at room temperature for 2 hours andrefluxed for 2 hours while stirring. After cooling it is filtered, theresidue washed with ethyl acetate and the filtrate evaporated in vacuo.The residue is treated with 10 ml. concentrated hydrochloric acid andextracted with ethyl acetate. The organic layer is separated, extractedwith 10% aqueous potassium carbonate and the aqueous solution acidifiedIwith hydrochloric acid. The precipitate formed is filtered off, washedwith water and recrystallized from aqueous ethanol to yield the2,4-dichloro-5-(4- methyl-phenylsulfamyl)-benzoic acid melting at 202-204.

EXAMPLE 5 According to the method shown in the previous examples thecompounds of Formula I, R '=furfuryl, R =R =H, R =Cl, and listed below,are prepared from 9 equivalent amounts of the corresponding startingmaterials of Formula III, R =X=Cl:

M.P. M.P. final starting Number Bi product material 1 4-CH30-CQH4 I208-209" 224226 2. 4F-CuH4 I 207208 231-233" 3- 2-Cl-C H4 I 201203168170 4. B-Cl-CJL I 216-2l8 190-192 5. 4-Cl-C;H I 218-220 238240 6.3-CFs-C5H4 I 230-232" 2142l6 7- 44313-05114 I 223 238-239 8- 4-NO2C6H4 I225 269271 9- Z-CflHi-CUH I 188-189 175-17 10.-- 4-HOCH2OH2-CIH I 178179196 198 11 4-(CHOzN-CeH I 218 l 168 12 3-CH5CONH-CrH I 147 238-241 13..3-NHz-C5H4 I 180 I 178-198 4-CH;C ON-CQH; I 252 246-247 15 4-CH3NH-C5H;l 199 I 140 I Decomposition. Norm-All compounds were recrystallized fromaqueous ethanol.

EXAMPLE 6 The mixture of 4.0 g.2,4-dichloro-5-(4-acetylaminophenylsulfamyl)-benzoic acid, 3.9 g.furfurylamine and ml. Z-methoxy-ethanol is refluxed for 4 hours undernitrogen. After cooling it is treated with 2 N-hydrochloric acid, theresidue formed separated and dissolved in 2N-aqueous sodium hydroxide.The solution is extracted with diethyl ether, the aqueous layerseparated, acidified with hydrochloric acid and the precipitate formedrecrystallized from aqueous ethanol to yield the N-furfuryl-4-chloro-5-(4-acetylamino phenylsulfamyl) anthranilic acid of the formula meltingat 248 with decomposition.

The starting material is prepared as follows: To the solution of 5.8 g.2,4-dichloro-5-chlorosulfonyl-benzoic acid in 50 ml. ethyl acetate, 12.0g. 4-aminoacetanilide are added, followed by 50 ml. ethyl acetate. Themixture is stirred for 2 hours at room temperature and refluxed for 2hours while stirring. After cooling to room temperature it is filtered,the residue (A) washed with ethyl acetate and the filtrate evaporated invacuo. The residue (B) is triturated with water and 10 ml. concentratedbydrochloric acid, filtered off, washed with water and dried. Thecombined residues (A) and (B) are dissolved in 60 ml. 10% aqueouspotassium carbonate, the solution washed with diethyl ether, acidifiedwith hydrochloric acid, the precipitate formed filtered off and washedwith water to yield the2,4-dichloro-5-(4-acetylamino-phenylsulfamyD-benzoic acid melting atabout 150.

EXAMPLE 7 drochloride of the formula NHOzS 00011 P HCl NHCH H N Clmelting at about 230.

EXAMPLE 8 The mixture of 6.5 g. 2,4-dichloro-S-phenysulfamylbenzoicacid, 8.0 g. tetrahydrofuryl-Z-methylamine and 30 ml. 2-methoxy-ethanolis refluxed for 4 hours under nitrogen. After cooling to roomtemperature, it is poured into 180 ml. 2 N-hydrochloric acid, theprecipitate separated, ground in a mortar, filtered, washed with waterand recrystallized several times from aqueous ethanol to yield the N(tetrahydrofuryl 2 methyl)-4-chloro-5- phenylsulfamyl-anthranilic acidof the formula melting at 238-239".

EXAMPLE 9 The mixture of 3.5 g. 2,4-dichloro-S-phenylsulfamylbenzoicacid, 4,6 g. (Z-methyl-tetrahydrofuryl-2)-methylamine and 10 ml.2-methoxy-ethanol is refluxed for 4 hours under nitrogen and stirredovernight at room temperature. Herenpon it is poured into ml. 2N-hydrochloric acid, the residue separated and dissolved in 2 N- COOH 'aqueous sodium hydroxide. The solution is washed with diethyl ether,filtered and acidified with concentrated hydrochloric acid. Theprecipitate formed is filtered off and recrystallized from aqueousethanol, to yield the N-(2- methyl tetrahydrofuryl 2methyl)4-chloro-5-phenylsulfamyl-anthranilic acid of the formula COOHCH: J NH-CH:

0 melting at 207-208.

EXAMPLE 10 The mixture of 6.5 g. 2,4-dichloroS-phenylsulfamylbenzoicacid, 9.05 g. 2,3dihydro-pyranyl2-methylamine and 30 ml.2-methoxy-ethanol is refluxed for 4 hours under nitrogen. After coolingto room temperature it is poured into 180 ml. 2 N-hydrochloric acid, theprecipitate formed filtered off, washed with Water and recrystallizedfrom aqueous ethanol, to yield theN-(2,3-dihydropyranyl-2-methyl)-4-chloro 5 phenysulfamyl benzoic acid ofthe formula melting at -l17 with decomposition.

EXAMPLE 11 -NHOzS I Cl precipitate formed is filtered off, trituratedwith 75 ml. cold isopropanol, filtered again and dried to yield thesodium salt of the N-furfuryl-4-chloro-S-phenylsulfamylanthranilic acid,melting at 244 to 246 with decomposition.

EXAMPLE 12 The mixture of 2.0 g.N-benzyl-4-chloro-S-phenylsulfamyl-anthranilic acid, 2 ml. acetic acidanhydride and 8 ml. pyridine is heated at the steam bath for 1 hour,cooled and poured into water. The mixture is slightly acidified withconcentrated hydrochloric acid, the precipitate formed filtered off anddissolved in ethanol. To the solution, water and a few dropshydrochloric acid are added, the precipitate formed filtered oil andagain recrystallized from aqueous ethanol to yield the N,N-bisacetyl-N-benzyl-4-chloro-S-phenylsulfamyl anthranilic acid of theformula CHr-O C (Elms-[Dimmer Cl- N-GH melting at 206-208.

EXAMPLE 13 The mixture of 113.3 g. 2,4-dichloro--phenylsulfamyl benzoicacid, 500 ml. Z-methoxy-ethanol and 126.0 g. furfurylamine is stirredand refluxed under nitrogen for 4 hours. The cold mixture is then slowlypoured into 2.5 liters 2 N hydrochloric acid while stirring. Theprecipitate formed is filtered off, washed with water and dissolved in 1liter 2 N aqueous sodium hydroxide. The dark solution obtained isextracted three times with 135 ml. methylene chloride each and theaqueous layer carefully acidified with concentrated hydrochloric acid.The precipitate formed is filtered off, dissolved in 1 liter ethanol,the solution decolorized with charcoal, filtered hot, the filtratecombined with 1 liter hot water and, upon cooling to theN-furfuryl-4-chloro-5 phenylsulfamyl anthranilic acid (Example 1)crystallizes. It is filtered off and dried; it melts at about 206, whichmelting point can be raised to 208-210 by another recrystallization.

The starting material is prepared as follows: The mixture of 150 g.2,4-dichloro-benzoic acid and 600 g. chlorosulfonic acid is heated to150-155 for 3 hours While stirring. Thereupon, 223 g. chlorosulfonicacid are distilled ofi in vacuo and the cold residue poured into amixture of 1.65 kg. ice and 125 ml. water. The precipitate formed isfiltered otf, washed with cold water, dissolved in 800 ml. ethylacetate, the solution dried, filtered, and the filtrate diluted with 600ml. ethyl acetate. To the solution obtained (containing the2,4-dichloro-5- chlorosulfonyl-benzoic acid), cooled in a water bath,the mixture of 216 g. analine and 220 ml. ethyl acetate is added at suchrate that the temperature stays below 30. The mixture is stirred for 4hours at 25-30, whereupon 4 g. charcoal are added. It is then filtered,the residue washed with 125 ml. ethyl acetate, the filtrate washed firstwith 450 ml. 3 N hydrochloric acid, then with 550 ml. water, and finallyextracted with 700 ml. 7% aqueous sodium carbonate. The aqueous extractis separated, carefully acidified with concentraetd hydrochloric acidand the precipitate formed filtered off and dried at 75 in vacuo, toyield the 2,4-dichloro-5-phenylsulfamyl-benzoic acid melting at 212-216.

EXAMPLE 14.-

The mixture of equivalent amounts of 2,4-dichloro-5-(2,3-dihydro-6-thianaphthylsulfamyl)-benzoic acid and 0.5 ml.benzylamine in 1 ml. Z-methoxy-ethanol is heated for 4 hours to 130.After cooling, 5 ml. 2 N hydrochloric acid and 5 ml. water are added,the precipitate formed filtered off, washed with water and trituratedwith 2 N 12 aqueous sodium hydroxide. The alkaline solution is filtered,the filtrate acidified with hydrochloric acid, the precipitate formedfiltered off, washed with water and dried, to yield theN-benzyl-4-chloro-5-(2,3-dihydro-6- thianaphthylsulfamyl)anthranilicacid of the formula s Nrro.s 00011 01- Nn-om melting at 150 withdecomposition.

The starting material is prepared as follows: To the solution of 1.9 g.6-amino-2,3-dihydro-thianaphthene in 25 ml. ethyl acetate and 3 ml.pyridine, 2.9 g. 2,4- dichloro-S-chlorosulfonylbenzoic acid are addedslowly while stirring. The mixture is stirred for 3 hours at roomtemperature and allowed to stand overnight. It is made strongly acidicwith hydrochloric acid, extracted with ethyl acetate, the extract washedwith water, dried and evaporated in vacuo. The residue is taken up in 1N aqueous sodium hydroxide, the solution filtered and the filtrateacidified. The precipitate formed is filtered off and recrystallizedfirst from aqueous ethanol and finally from methanol, to yield the2,4-dichloro-5-(2,3-dihydro-6- thianaphthylsulamyl)-benzoic acid.

EXAMPLE 15 The mixture of 3.6 g. 2,4-dichloro 5 (N-methyl-N-phenylsulfamyD-benzoic acid, 3.9 g. furfurylamine and 10 ml.Z-methoxyethanol is refluxed for 4 hours under nitrogen. After cooling,it is poured into 50 ml. 2 N hydrochloric acid, the precipitate formedfiltered off, washed with water and heated with 50 ml. 2 N aqueoussodium hydroxide. To the suspension obtained, water and diethyl etherare added until 2 clear layers are formed. The aqueous layer isseparated, washed with diethyl ether and acidified with hydrochloricacid. The precipitate formed is filtered off and recrystallized fromaqueous ethanol, to yield theN-furfuryl-4-chloro-5-(N-methyl-N-phenylsulfamyl)-anthranilic acid ofthe formula (Ill-I: Q-NOzS-QC 0 0H -II melting at 171-172.

In the analogous manner, the N-benzyl-4-chloro-5-(N-methyl-N-phenylsulfamyl)-anthranilic acid is obtained; M.P. 164-166".

The starting material is prepared as follows: To the solution of 11.6 g.2,4-dichloro-5-chlorosulfonyl-benzoic acid in ml. ethyl acetate, 17.1 g.N-methyl-aniline are added slowly, and the mixture is stirred at roomtemperature for 4 hours. It is then filtered, the filtrate evaporated invacuo and the residue taken up in water and 20 ml. concentratedhydrochloric acid. The mixture is extracted with ethyl acetate, theextract washed with water and shaken with 10% aqueous potassiumcarbonate. The aqueous layer is separated, acidified with concentratedhydrochloric acid, the precipitate formed filtered oil? andrecrystallized from aqueous ethanol to yield the 2,4-dichloro 5(N-methyl-N-phenylsulfamyl)-benzoic acid, melting at 170-171".

EXAMPLE 16 The mixture of 3 g. N-benzyl-4-chloro-5-(N-methyl-N-phenylsulfamyl)-anthranilic acid (Example 15), 12 ml. pyridine and 3 ml.acetic acid anhydride is heated at the steam bath for 1 hour whilestirring. After cooling, it is poured into ml. water, the mixtureacidified with concentrated hydrochloric acid, the precipitate collectedand recrystallized from aqueous methanol to yield the N- 13acetyl-N-benzyl-4-chloro 5 (N methyl-N-phenylsulfamyD-anthranilic acidof the formula H: NOgS CODE 01 N-CH o-crn melting at 176-177 withdecomposition.

EXAMPLE 17 anthranilic acid of the formula COOH N-CHr- NHOS melting at183-184 with decomposition.

EXAMPLE 18 The mixture of 3 g. N methyl-N-benzyl-4-chloro-S-phenylsulfamyl-anthranilic acid (Example 17), 12 ml. pyridine and 3 ml.acetic acid anhydride is heated at the steam bath for 1 hour whilestirring. After cooling, it is poured into 120 ml. water, the mixtureacidified with concentrated hydrochloric acid and the precipitate formedfiltered off. The residue is dissolved in the minimum amount of hotethanol, the solution filtered and allowed to cool to room temperature.The precipitate formed is filtered oh and washed with aqueous ethanol toyield the N-methyl-N-benzyl 4 chloro-S-(N-acetyl N phenylsulfamyl)-anthranilic acid of the formula CHa-CO N 028 C 0 OH C N-CH n, meltingat 191-492 with decomposition.

EXAMPLE 19 Preparation of 10,000 tablets each containing 50.0 mg. of theactive ingredient:

Purified water, q.s.

Procedure-All the powders are passed through a screen with an opening of0.6 mm. Then the drug' substance, lactose, talcum, magnesium stearateand half of the starch are mixed in a suitable mixer. The other half ofthe starch is suspended in 45 ml. water and the suspension added to theboiling solution of the polyethylene glycol in 180 ml. water. The pasteformed is added to the powders which are granulated, if necessary, withan additional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm. openings and compressed into tabletsusing concave punches with 7.1 mm. diameter, uppers bisected.

EXAMPLE 20 The mixture of 2.2 g. methyl4-chloro-S-phenylsulfamylanthranilate and 12 ml. benzaldehyde is heatedto 200 C. for 1 hour and evaporated in vacuo. The residue is trituratedWith ml. ethylacetate, filtered off and the filtrate hydrogenated over0.3 g. platinum dioxide at room temperature until the hydrogen uptakeslows down (/2 hour). The mixture is filtered, the filtrate evaporatedin vacuo, the residue taken up in chloroformdiethylamine (9:1) andchromatographed on silica gel, to yield as the main eluate the amorphousmethyl N-benzyl-4-chloros-phenylsulfamyl-anthranilate of the formulaNHOz S C O O CH:

Cl NH-CH:

showing in the I.R.-spectrum bands, inter alia at 1750 and 1250 cm.-

1.8 g. thereof are dissolved in 20 ml. methanol and 10 ml. 2 N aqueoussodium hydroxide, and the solution is refluxed for 20 minutes. It isthen concentrated in vacuo, the aqueous concentrate diluted with water,extracted with diethyl ether and the aqueous layer acidified withhydrochloric acid. The precipitate formed is filtered off andrecrystallized from aqueous ethanol, to yield the N-benzyl- 4-chloro 5phenylsulfamyl-anthranilic acid melting at 226-228; it is identical withthe product obtained according to Example 3.

The starting material is prepared as follows: The mixture of 1.0 g.2,4-dichloro-S-phenylsulfamyl-benzoic acid and 25 ml. concentratedaqueous ammonia is heated in a sealed tube to for 4 hours. Hereupon, itis evaporated in vacuo, the residue taken up in 25 ml. saturatedanhydrous methanolic hydrochloric acid and the mixture gently refluxedfor 1 hour. It is evaporated in 'vacuo and the residue recrystallizedfrom methanol, to yield the methyl 4-chloro5-phenylsulfamyl-anthranilate melting at l83186.

EXAMPLE 21 The mixture of 2.0 g. methyl 4-chloro-5-phenylsulfamylanthranilate and 5 ml. benzyl chloride is refluxed for 2 hours andevaporated in vacuo. The residue is triturated with diethyl ether,filtered OE and washed with diethyl ether to yield the methylN-benzyl-4-chloro-5-phenylsulfamyl-anthranilate melting at about 200(softening at it is identical with the compound obtained according toExample 20.

The mixture of 1.3 g. thereof, 5 ml. methanol, 5 ml. water and 1.5 ml. 6N aqueous sodium hydroxide is heated at the steam cone for 30 minutesand allowed to stand at 25 for 1 hour. It is then concentrated in vacuo,the concentrate diluted with Water, extracted with diethyl ether and theaqueous layer filtered. The filtrate is acidified with hydrochloric acidto pH 5, the precipitate formed filtered off and recrystallized fromaqueous ethanol, to yield theN-benzyl-4-chloro-5-phenylsulfamyl-anthranilic acid melting at 226; itis identical with the product obtained according to Example 3.

EXAMPLE 22 To the suspension of 4.07 g.N-furfuryl-S-phenylsulfamyl-4chloro-anthranilic acid and 50 ml.methanol, 0.61 g. 2-hydroxy-ethylamine are added while stirring. Theresulting yellowish solution is evaporated in vacuo, to yield the2-hydroxyethyl-ammonium N furfuryl-S-phenylsulfamyl-4-chloro-anthranilate of the formula HNOzS- C OONHa-CHz-CH2OH melting at 90.

1 EXAMPLE 23 The mixture of 13.1 g. ethyl2,4-dichloro-5-phenylsulfamylbenzoate and 20.4 g. furfurylamine isheated for 1 hour to 110. After cooling, it is poured into 210 ml.water, the mixture acidified with glacial acetic acid to pH 4.5 whilekeeping the temperature 'below 20. The precipitate formed is filtered01f, washed with water and suspended in 250 ml. 0.5 N sodium hydroxidewhile stirring at room temperature. It is filtered, the residuesuspended in water and the mixing acidified with hydrochloric acid to pH2 while stirring. It is again filtered and the residue recrystallizedseveral times from aqueous ethanol and finally from anhydrous ethanol,to yield the ethyl N-furfuryl-5-sulfamyl-4-chloro-anthranilate of theformula melting at 157-159.

The starting material is prepared as follows: The mixture of g.2,4-dichloro-5-phenylsulfamyl-benzoic acid and 150 ml. 6 N ethanolichydrochloric acid is refluxed for 90 minutes and allowed to stand in thecold. The precipitate formed is filtered off, and recrystallized fromaqueous ethanol, to yield the ethyl2,4-dichloro-5-phenylsulfamyl-benzoate melting at 132-133.

EXAMPLE 24 The mixture of 6.6 g. 2,4-dichloro-5-phenylsulfamylbenzoicacid 3-dimethylamino-propylamide, 5.8 g. furfurylamine and 15 ml.Z-methoxy-ethanol is refluxed for 4 hours under nitrogen and evaporatedin vacuo. The residue is taken up in 100 ml. 2 N aqueous sodiumhydroxide and the mixture extracted with ethyl acetate. The organiclayer is dried, filtered and evaporated. The residue is triturated withhydrogen chloride in ethyl acetate, the precipitate formed filtered offand taken up in water. The solution is washed with ethyl acetate,filtered and made basic With 2 N aqueous sodium hydroxide. The mixtureis extracted with ethyl acetate, the extract dried, filtered andevaporated, to yield the amorphous N-furfurylS-phenylsulfamyl-4-chloroanthranilic acid 3-dimethylaminopropylamide ofthe formula showing in the thin layer chromatogram on silica gel inchloroform, methanol and diethylamine (85:5:10) an R =7.5.

The starting material is prepared as follows: To the mixture of 17.7 g.2,4-dichloro-S-phenylsulfamyl-benzoic acid and 90 ml.1,2-dimethoxyethane, 24 ml. thionyl chloride are added dropwise during25 minutes while stirring, the whole is refluxed for 90 minutes andevaporated in vacuo. 18.6 g. of the resulting acid chloride is taken upin 300 ml. ethyl acetate and the solution added dropwise to the mixtureof 11.8 g. 3-dimethylaminopropylamine and 450 ml. ethyl acetate whilestirring, and stirring is continued overnight at room temperature. Themixture is filtered, the filtrate acidified with hydrogen chloride inethyl acetate and the precipitate formed filtered off. It is taken up inwater, the solution washed with ethyl acetate and made alkaline with 10%potassium carbonate. The mixture is extracted with ethyl acetate, themixture dried, filtered and evaporated, to yield the2,4-dichloro-5-phenylsulfamyl-benzoic acid 3-dimethylamino-propylamidemelting between about 80 and 90?.

1 6 EXAMPLE 2s The mixture of 3.6 g.2,4-dichloro-5-(4-hydroxyphenylsulfamyl)-benzoic acid, 10 ml.2-rnethoxy-ethanol and 3.9 g. furfurylamine is refluxed for 4 hoursunder nitrogen. After cooling, it is poured into 50 ml. 2 N hydrochloricacid, the precipitate formed filtered off, washed with water and takenup in 2 N aqueous sodium hydroxide. The mixture is washed with diethylether, filtered and the filtrate acidified with concentratedhydrochloric acid. The precipitate formed is filtered OE andrecrystallized from aqueous ethanol, to yield theN-furfuryl-4-chloro-5-(4-hydroxyphenylsulfamyl)-anthrani1ic acid of theformula melting at 227 with decomposition.

The starting material is prepared as follows: To the mixture of 5.8 g.2,4-dichloro-S-chlorosulfonyl-benzoic acid and ml. ethyl acetate, 8.7 g.4-hydroxyaniline are added portionwise and the mixture stirred at roomtemperature for 4 hours. After standing overnight, it is filtered, theresidue suspended in 50 ml. water, the mixture acidified with 10 ml.concentrated hydrochloric acid and extracted with ethyl acetate. Theextract is filtered, washed with water and shaken with 10% aqueouspotassium carbonate. The aqueous solution is filtered, acidified withconcentrated hydrochloric acid and the precipitate formed filtered oil.It is recrystallized several times from aqueous ethanol, to yield the2,4-dichloro-5-(4-hydroxyphenylsulfamy1)-benzoic acid melting at 223-235EXAMPLE 26 In the manner described in Example 25, the N-furfuryl-4-ch1oro-5-(2-hydroxyphenyl-sulfamyl) anthranilic acid, M.P. (dec.) andthe N-furfuryl-4-chloro-5-(3-hydroxyphenylsulfamyl)-anthranilic acid,M.P. 202 (dec.) are prepared from the same amounts of the correspondingisomeric starting materials, which melt at 187-189" and 192-194respectively.

EXAMPLE 27 The mixture of 3.9 g.2,4-dichloro-5-(3,4-dimethoxyphenylsulfamyl)-benzoic acid, 10 ml.2-methoxyethanol and 3.7 g. furfurylamine is refluxed for 4 hours undernitrogen. After cooling, it is poured into 50 ml. 2 N hydrochloric acid,the precipitate formed filtered off, washed with water and taken up in 2N aqueous sodium hydroxide. The mixture is washed with diethyl ether,filtered, the filtrate acidified with concentrated hydrochloric acid,tht precipitate formed collected and recrystallized two times fromaqueous ethanol, to yield the N-furfuryl-4-chloro-S-(3,4-dimethoxyphenylsulfamyl)-anthranilic acid of the formulaCH:O- HNOzS- CODE 71 CH: 0- C1- NH-CH:L

melting at 123.

The starting material is prepared as follows: To the solution of 12.3 g.3,4-dimethoxyaniline and 50 ml. ethyl acetate, 5.8 g.2,4-dichloro-S-chlorosulfonyl-benzoic acid are added while stirring, andthe mixture stirred for 4 hours at room temperature. It is filtered, theresidue washed with ethyl acetate and the filtrate combined with 10 ml.water and concentrated hydrochloric acid each and diluted with ethylacetate. The organic layer is separated, extracted with 10% aqueouspotassium carbonate and the extract acidified with concentratedhydrochloric acid. The precipitate formed is filtered off andrecrystallized two times from aqueous ethanol, to yield the2,4-dichloro-5-(3-dimethoxyphenylsulfamyl)benzoic acid melting at202203.

EXAMPLE 2:;

In the manner described in Example 27, the N-furfuryl- 4-chloro-5-(2,4dimethoxyphenylsulfamyl) anthranilic acid, M.P. 103 and theN-furfuryl-4-chloro-5-(2,5-dimethoxyphenylsulfamyl)-anthranilic acid,M.P. l99-202 are prepared from the same amounts of the correspondingisomeric starting materials, which melt at 184185 and 180-182respectively.

EXAMPLE 29 Analogous to the procedures illustrated in the previousexamples, more particularly according to Example 25, the N-furfuryl 4chloro-S-[4-mercaptophenyl, 3,4-dihydroxyphenyl,3-methyl-4-hydroxyphenyl, 3-methoxy 4- hydroxyphenyl,4-(2-hydroxyethyl)-phenyl, 4-(2-hydroxyethoxy)-phenyl, 4-carboxyphenyl,4-carbomethoxyphenyl or 4-carbethoxyphenyl]-sulfamyl-anthranilic acidor, according to Example 7, the N-furfuryl-4-chloro-5-[2- or3-aminophenyl, 3,5-diaminophenyl, 4-dimethylaminophenyl or4-diethylaminophenyl]-sulfamyl-anthranilic acid, their sodium, potassiumor 2-ethanol-ammonium salts or the hydrochlorides of the aminophenylcompounds, are prepared from equivalent amounts of the correspondingstarting materials.

EXAMPLE 30 Preparation of 1,000 capsules, each containing 25 mg. of theactive ingredient:

Formula: G.

N-furfuryl 4 chloro-S-(4-hydroxyphenylsulfamyl)-anthranilic acid 25.0

Lactose 220.0

Procedure:

The ingredients are intimately mixed in a suitable mixer, passed througha screen with openings of 0.6 mm., remixed and 245 mg. are filled intoNo. 3 hard shell gelatin capsules.

In the analogous manner, capsules are prepared containing per unit 75mg. N-furfuryl-4-chloro-5-(4-methoxyphenylsulfamyl)-anthranilic acid orN-furfuryl-4-chloro- 5-(4-aminophenylsulfamyl)-anthrani1ic acidhydrochloride and 170 mg. lactose.

EXAMPLE 31 Preparation of 10,000 tablets, each containing 50 mg. of theactive ingredient:

Formula: G.

N furfuryl 4 chloro-S-phenylsulfamylanthranilic acid 500.0 Lactose2,500.0 Microcrystalline cellulose 1,000.0 Corn starch 160.0 Magnesiumstearate 40.0

Purified water, q.s.

Procedure-All the powders, except the starch and the magnesium stearate,are passed through a screen with 0.6 mm. openings and mixed in asuitable mixer. The starch is suspended in 160 ml. water and thesuspension added to 200 ml. boiling water. The paste formed is added tothe powders which are granulated, if necessary, with an additionalamount of water. The granulate is dried overnight at 35, broken on ascreen with 1.2 mm. openings, the magnesium stearate added, mixed welland the granulate compressed into 420 mg. tablets using concave puncheswith 7.1 mm. diameter, uppers bisected.

EXAMPLE 32 The mixture of 15 g. ofN-furfuryl-4-chloro-5-(2-acetylaminophenylsulfamyl)-anthranilic acid and90 m1. of 2 N aqueous sodium hydroxide are refluxed for 2% hours in anitrogen atmosphere, cooled and acidified with glacial acetic acid. Thesolids formed are collected on a filter, washed with water andrecrystallized from aqueous ethanol 18 to aflord theN-furfuryl-4-chloro-5-(Z-aminophenylsulfamyl)-anthranilic acid of theformula O-HNOzS COOH W NH: Cl NHCH2 O melting at 246248.

The starting material is prepared as follows:

To the solution of 50 g. of 2-aminoacetanilide and 100 ml. ofdimethylformamide are added portionwise 30 g. of2,4-dichloro-S-chlorosulfonyl-benzoic acid at 20. The reaction mixtureis warmed to 40 for 2 hours, evaporated under reduced pressure and theresidue poured into 500 ml. of water and 7 ml. of concentratedhydrochloric acid. The solids formed are collected on a filter, washedwith water and dilute aqueous hydrochloric acid, and triturated withaqueous ethanol to give the 2,4-dichloro-5-(2-acetylaminophenylsulfamyl)-benzoic acid melting at 222- 225.

The mixture of 30 g. thereof, 30 g. of furfurylamine and 75 ml. of2-methoxy-ethan0l is refluxed for 4 hours under nitrogen. The mixture isconcentrated to half its volume under reduced pressure and is thenpoured onto 250 ml. of 2 N aqueous hydrochloric acid with stirring. Theprecipitate formed is filtered, Washed with water, triturated with a 1:1mixture of ethanol and Water at 70 and repeated with aqueous methanol togive the N- furfuryl-4-chloro 5 (Z-acetylaminophenylsulfamyl)-anthranilic acid melting at 221-225.

EXAMPLE 33 The mixture of 5.5 g. of2,4-dichloro-5-(4-carbethoxyphenylsulfamyyl)-benzoic acid, 10 ml. of2-methoxyethanol and 5 g. of furfurylamine is refluxed for 4 hours undernitrogen. After cooling, it is poured onto 50 ml. of 2 N aqueoushydrochloric acid. The precipitate formed is filtered, washed with waterand taken up in 2 N aqueous sodium hydroxide. The mixture is washed withdiethyl ether, filtered and the filtrate acidified with concentratedhydrochloric acid. The precipitate formed is collected on a filter andrecrystallized from aqueous ethanol, to yield the N-furfuryl-4-chloro 5(4-carbethoxyphenyl sulfamyl)-anthranilic acid of the formula @AINWS-QCQOH CzH5O 0 o 01- NH-CH i melting at 217 with decomposition.

The starting material is prepared as follows:

To the solution of 16.5 g. of 4-aminobenzoic acid ethyl ester in ml. ofethyl acetate is added portionwise at room temperature 7.2 g. of2,4-dichloro-5-chlorosulfonylbenzoic acid. The mixture is allowed tostir for one hour at room temperature, then refluxed for 6 hours. Aftercooling, the solids are filtered off and washed with ethyl acetate. Thefiltrate is evaporated under reduced pressure. The residue is treatedwith water and 15 ml. of concentrated hydrochloric acid and thenextracted with ethyl acetate. The ethyl acetate solution is extractedwith 3 portions, 50 ml. each, of 10% aqueous potassium carbonate. Thecarbonate extracts are combined, filtered and acidified withconcentrated hydrochloric acid. The precipitate formed is filtered,washed and recrystallized from aqueous ethanol to afford the2,4-dichloro-5-(4-carbethoxyphenylsulfamyl)-benzoic acid melting at226-228.

EXAMPLE 34 In an analogous manner as in Example 33, 4.7 g. of2,4-dichloro 5 (4-carboxyphenylsulfamyl)-benzoic acid reacted with 4.7g. of furfurylamine in 10 ml. of 2-methoxy-ethanol aflords onrecrystallization from aqueous eth- 19 anol theN-furfuryl-4-chloro-5-(4-carboxyphenylsulfamyl)-anthranilic acid meltingat 264 with decomposition. The starting material is prepared by thehydrolysis of the 2,4-dichloro 5 (4-carbethoxyphenylsulfamyl)-benzoicacid (Example 33) and melts at 288 with decomposition.

EXAMPLE 35 The mixture of 5 g. of N-(4-carboxyphenyl)-2,4-dichloro-S-(4carboxyphenylsulfamyl)-benzamide, 5 g. of furonto 50 m1. of 2 N aqueoushydrochloric acid. The prefor 4 hours under nitrogen. After cooling, itis poured onto 50 ml. of 2N aqueous hydrochloric acid. The precipitateformed is filtered, washed with water and taken in 2 N aqueous sodiumhydroxide. The mixture is washed with diethyl ether, filtered and thefiltrate acidified with concentrated hydrochloric acid to precipitate asyrupy material. The mixture is decanted and the product treated with a1:1 mixture of ethanol and water. Recrystallization of the solids from a1:1 ethanol-water mixture gives as a first crop theN-(4-carboxyphenyl)-2-(N-furfurylamino)-4-chloro 5(4-carboxyphenylsulfamyl)-anthranilamide of the formula 0 ONHC 0 on Omelting at 246 with decomposition. The material obtained on evaporationof the recrystallization solvent corresponds to the product of Example34.

The starting material is prepared as follows:

The solution of 7.2 g. of 4-aminobenzoic acid in 150 ml. of ethylacetate is treated with 7.2 g. of 2,4-dichloro- -chlorosulfonyl-benzoicacid. The mixture is then refluxed for 6 hours. After cooling, thesolids are filtered ofl and washed with ethyl acetate. The filtrate isevaporated under reduced pressure. The residue is treated with water andml. of concentrated hydrochloric acid and then extracted with ethylacetate. The ethyl acetate solution is extracted with 3 portions, 50 ml.each, of 10% aqueous potassium carbonate. The carbonate extracts arecombined, filtered and acidified with concentrated hydrochloric acid.The crystalline material obtained is ground and treated with a 1:2ethanol-water mixture, filtered, washed and dried to afford a mixture ofN-(4-carboxyphenyl)-2,4-dichloro-5-(4 carboxyphenylsulfamyl)-benzamideand the 2,4-dichloro-5-(4-carboxyphenylsulfamyl)- benzoic acid.

20 What is claimed is: 1. A S-arylsulfamyl-2,4-dihalobenzoic acid of theformula COOH in which X is fluoro or chloro, R is chloro or bromo, R ishydrogen or lower alkanoyl and R is phenyl and phenyl substituted withone or two lower alkyls, hydroxyls, lower alkoxies, halogens or amines,and phenyl substituted with one lower hydroxy-alkyl, lowerhydroxyalkoxy, trifluoromethyl, nitro, di-lower alkylamino or loweralkanoylamino, and phenyl substituted with one lower alkyl and onehydroxy, or one lower alkoxy and one hydroxy moiety, or the methyl orethyl ester, the sodium or O- tassium salt of the carboxylic acids orthe hydrochlorides of the monoor diamino or di-lower alkylaminocompounds.

2. A compound as claimed in claim 1, in which formula each of X and R ischloro and R and R have the meaning given in claim 1.

3. A compound as claimed in claim 1, and being the2,4-dichloro-S-phenylsulfamyl-benzoic acid.

4. A compound as claimed in claim 1, and being the2,4-dichloro-5-(4-hydroxy-, methoxyor aminophenylsulfamyD-benzoic acidor the sodium or potassium salt thereof or the hydrochloride of theamino compound.

5. A compound as claimed in claim 1 in which formula each of X and R ischloro, R is hydrogen or acetyl and R is phenyl and phenyl substitutedwith one or two methyls, hydroxyls, methoxies or amines, and phenylsubstituted with one 2-hydroxyethyl, Z-hydroxyethoxy, fluoro, chloro,trifluoromethyl, nitro, dimethylamino or acetylamino, and phenylsubstituted with one methyl and one hydroxy, or one methoxy and onehydroxy moiety, or the methyl or ethyl ester, the sodium or potassiumsalt of the carboxylic acids or the hydrochlorides of the monoor diaminoor dimethylamino compounds.

6. A compound as claimed in claim 1, and being the 2,4-dichloro 5(2-acetylaminophenylsulfamyl)-benzoic acid.

References Cited UNITED STATES PATENTS 3,470,155 9/1969 Weinstock260-518 A LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON,Assistant Examiner US. Cl. X. R.

UNITED STATES PATENT OFFICE CASE SU- 489/ 1-H CERTIFICATE OF CORRECTIONPatent No. 3 5 Dated April 3 97 Inventor(s) LINCOLN HARVEY WERNER It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 20, claim 1, amend the formula to read as follows:

R5-NO S COOH Signed and sealed this 29th day of October 1974.

(SEAL) Atteet:

McCOY M. GIBSON JR. 0. MARSHALL DANN Attesting Officer Commissioner ofPatents

